1. Field of the Invention
This invention is directed to the polymeric matrices that include poly(ester amides) to control the release profiles of agents from within these matrices.
2. Description of the State of the Art
Biomaterial research scientists are striving to improve the compositions from which medical devices and coatings are produced. For example, the control of protein adsorption on an implant surface and the local administration of agents from an implant are areas of focus in biomaterials research. Uncontrolled protein adsorption on an implant surface, for example, leads to a mixed layer of partially denatured proteins on the implant surface. This mixed layer of partially denatured proteins can lead to disease by providing cell-binding sites from adsorbed plasma proteins such as fibrinogen and immunoglobulin G. Platelets and inflammatory cells such as, for example, monocytes, macrophages and neutrophils, adhere to the cell-binding sites. A wide variety of proinflammatory and proliferative factors may be secreted and result in a diseased state. Accordingly, a non-fouling surface, which is a surface that does not become fouled or becomes less fouled with this layer of partially denatured proteins, is desirable.
A stent is an example of an implant that can benefit from improvements such as, for example, a non-fouling surface and a coating that can be used as a vehicle for delivering pharmaceutically active agents in a predictable manner. Stents can act as a mechanical intervention to physically hold open and, if desired, expand a passageway within a subject. Typically, a stent may be compressed, inserted into a small vessel through a catheter, and then expanded to a larger diameter once placed in a proper location. Examples of patents disclosing stents include U.S. Pat. Nos. 4,733,665, 4,800,882 and 4,886,062.
Stents play an important role in a variety of medical procedures such as, for example, percutaneous transluminal coronary angioplasty (PTCA), which is a procedure used to treat heart disease. In PTCA, a balloon catheter is inserted through a brachial or femoral artery, positioned across a coronary artery occlusion, inflated to compress atherosclerotic plaque and open the lumen of the coronary artery, deflated and withdrawn. Problems with PTCA include formation of intimal flaps or torn arterial linings, both of which can create another occlusion in the lumen of the coronary artery. Moreover, thrombosis and restenosis may occur several months after the procedure and create a need for additional angioplasty or a surgical by-pass operation. Stents are generally implanted to reduce occlusions, inhibit thrombosis and restenosis, and maintain patency within vascular lumens such as, for example, the lumen of a coronary artery.
Improvements to stents are also being developed to provide a controlled, local delivery of agents. Local delivery of agents is often preferred over systemic delivery of agents, particularly where high systemic doses are necessary to achieve an effect at a particular site within a subject—high systemic doses of agents can often create adverse effects within the subject. One proposed method of local delivery includes coating the surface of a medical article with a polymeric carrier and attaching an agent to, or blending it with, the polymeric carrier.
Agent-coated stents have demonstrated dramatic reductions in the rates of stent restenosis by inhibiting tissue growth associated with the restenosis. Restenosis is a complex biological process and agents have been applied in combination in an attempt to circumvent the process of restenosis. One method of applying multiple agents involves blending the agents together in one formulation and applying the blend to the surface of a stent in a polymer matrix. A disadvantage of this method is that the agents are released from the matrix through the blend and compete with one another for release.
The process of restenosis in coronary artery disease is derived from a complex interplay of several implant-centered biological parameters. These are thought to be the combination of elastic recoil, vascular remodeling, and neo-intimal hyperplasia. Since restenosis is a multifactorial phenomenon, the local agent delivery of agents from a stent would benefit from the design of a release rate profile that would deliver agents as needed from the stent in a controlled and predictable manner.
Stents are used in the treatment and ameliorization of symptoms of other disorders that include, but are not limited to, tumors in organs such as, for example, bile ducts, esophagus, trachea/bronchi, benign pancreatic disease, coronary artery disease, carotid artery disease, and peripheral arterial disease. Peripheral arterial diseases include, but are not limited to, atherosclerosis, restenosis and vulnerable plaque. Vulnerable plaque is a type of fatty build-up in an artery thought to be caused by inflammation and is covered by a thin fibrous cap that can rupture leading to blood clot formation. The treatment of these and other conditions can benefit from localized delivery of an agent.
Unfortunately, the art has not yet developed a reliable way to control the release of agents from a medical device or coating, yet such control can be important to obtaining the desired effects or reducing any adverse effects that may otherwise occur from administration of the agents. In addition to providing a way to improve, for example, the therapeutic and diagnostic results currently obtained from the administration of agents, control over the release of agents can assist in designing and maintaining the physical and mechanical properties of medical devices and coatings as well. Accordingly, control over the release of agents is an important design consideration and one of the next hallmarks in the development of stent technology.